Synthesis and antiviral evaluation of a mutagenic and non-hydrogen bonding ribonucleoside analogue: 1-β-D-ribofuranosyl-3-nitropyrrole

Daniel A. Harki, Jason D. Graci, Victoria S. Korneeva, Saikat Kumar B. Ghosh, Zhi Hong, Craig Eugene Cameron, Blake R. Peterson

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Synthetic small molecules that promote viral mutagenesis represent a promising new class of antiviral therapeutics. Ribavirin is a broad-spectrum antiviral nucleoside whose antiviral mechanism against RNA viruses likely reflects the ability of this compound to introduce mutations into the viral genome. The mutagenicity of ribavirin results from the incorporation of ribavirin triphosphate opposite both cytidine and uridine in viral RNA. In an effort to identify compounds with mutagenicity greater than that of ribavirin, we synthesized 1-β-D-ribofuranosyl-3-nitropyrrole (3-NPN) and the corresponding triphosphate (3-NPNTP). These compounds constitute RNA analogues of the known DNA nucleoside 1-(2′-deoxy-β-D-ribofuranosyl)-3-nitropyrrole. The 3-nitropyrrole pseudobase has been shown to maintain the integrity of DNA duplexes when placed opposite any of the four nucleobases without requiring hydrogen bonding. X-ray crystallography revealed that 3-NPN is structurally similar to ribavirin, and both compounds are substrates for adenosine kinase, an enzyme critical for conversion to the corresponding triphosphate in cells. Whereas ribavirin exhibits antiviral activity against poliovirus in cell culture, 3-NPN lacks this activity. Evaluation of 3-NPNTP utilization by poliovirus RNA-dependent RNA polymerase (RdRP) revealed that 3-NPNTP was not accepted universally. Rather, incorporation was only observed opposite A and U in the template and at a rate 100-fold slower than the rate of incorporation of ribavirin triphosphate. This diminished rate of incorporation into viral RNA likely precludes 3-NPN from functioning as an antiviral agent. These results indicate that hydrogen bonding substituents are critical for efficient incorporation of ribonucleotides into RNA by viral RdRPs, thus providing important considerations for the design of improved mutagenic antiviral nucleosides.

Original languageEnglish (US)
Pages (from-to)9026-9033
Number of pages8
JournalBiochemistry
Volume41
Issue number29
DOIs
StatePublished - Jul 23 2002

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Ribonucleosides
Ribavirin
Antiviral Agents
Viral RNA
Nucleosides
Poliovirus
Hydrogen Bonding
Hydrogen bonds
Adenosine Kinase
RNA
Ribonucleotides
RNA Replicase
Cytidine
Mutagenesis
Viral Genome
Uridine
RNA Viruses
X ray crystallography
X Ray Crystallography
DNA

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Harki, D. A., Graci, J. D., Korneeva, V. S., Ghosh, S. K. B., Hong, Z., Cameron, C. E., & Peterson, B. R. (2002). Synthesis and antiviral evaluation of a mutagenic and non-hydrogen bonding ribonucleoside analogue: 1-β-D-ribofuranosyl-3-nitropyrrole. Biochemistry, 41(29), 9026-9033. https://doi.org/10.1021/bi026120w
Harki, Daniel A. ; Graci, Jason D. ; Korneeva, Victoria S. ; Ghosh, Saikat Kumar B. ; Hong, Zhi ; Cameron, Craig Eugene ; Peterson, Blake R. / Synthesis and antiviral evaluation of a mutagenic and non-hydrogen bonding ribonucleoside analogue : 1-β-D-ribofuranosyl-3-nitropyrrole. In: Biochemistry. 2002 ; Vol. 41, No. 29. pp. 9026-9033.
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Harki, DA, Graci, JD, Korneeva, VS, Ghosh, SKB, Hong, Z, Cameron, CE & Peterson, BR 2002, 'Synthesis and antiviral evaluation of a mutagenic and non-hydrogen bonding ribonucleoside analogue: 1-β-D-ribofuranosyl-3-nitropyrrole', Biochemistry, vol. 41, no. 29, pp. 9026-9033. https://doi.org/10.1021/bi026120w

Synthesis and antiviral evaluation of a mutagenic and non-hydrogen bonding ribonucleoside analogue : 1-β-D-ribofuranosyl-3-nitropyrrole. / Harki, Daniel A.; Graci, Jason D.; Korneeva, Victoria S.; Ghosh, Saikat Kumar B.; Hong, Zhi; Cameron, Craig Eugene; Peterson, Blake R.

In: Biochemistry, Vol. 41, No. 29, 23.07.2002, p. 9026-9033.

Research output: Contribution to journalArticle

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AU - Harki, Daniel A.

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AU - Cameron, Craig Eugene

AU - Peterson, Blake R.

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